In order to fulfill an inherent function of an active ingredient contained in a formulation or a health food without excessively taking it, it is necessary to enhance the bioavailability for the formulation or the health food. Taking the formulation as an example, while an oral formulation has the advantages of being convenient and causing little distress compared to an injectable formulation, it has the disadvantage of providing low bioavailability. The oral formulation enters into the intestine via the stomach and the duodenum, is absorbed into blood mainly through the intestinal tract and then is delivered to the liver via the portal vein. A part of the oral formulation is decomposed by undergoing the action of a gastric acid or the like or being metabolized in the liver during passing through such a long path, whereby converted into a totally different substance. One of the major reasons for the low bioavailability is that the oral formulation is difficult to be absorbed from digestive organs like the intestine. In order to enhance the bioavailability for the formulation, it is necessary to get the size down of the organic compound with medicinal ingredients to a level required to facilitate the absorption of the compound from the digestive organs into the blood.
In the case of the injectable formulation, a typical example of parenteral formulations, effective functioning of a medicinal ingredient in the formulation requires the reaching of the medicinal ingredient through blood vessels in the body to a target site. The inner diameter of a capillary blood vessel, which is the narrowest among the blood vessels, is about 5 μm. Accordingly, in order to make pass the organic compound with the medicinal ingredient through the capillary blood vessel without causing occlusion, the particle diameter of this organic compound needs to be 5 μm or less. Further, for the same reason as the oral formulation, it is necessary for a health food to get the size down of the organic compound with active ingredients to a level required to facilitate the absorption of the compound from the digestive organs into the blood.
In the case of a solid skin-lightening ingredient and a moisturizing ingredient contained in a cosmetic, less agglomeration and the smaller particle size are required in order to make them easily attached and thinly spread on a skin surface while if it is in the form of a milky lotion, not to cause phase separation in a container in which this cosmetic is contained so that a uniform dispersion state may be sustainable.
In accordance with recent development of a nanotechnology, the preparation of the nano-sized organic compound to satisfy the requirements as mentioned above has attracted high attention. For example, a particulate formulation which contains a steroid or a steroid derivative with median of the particle distribution in the range of 0.005 to 5 μm and with the 90%-diameter of 10 μm or less has been known (for example, see Patent Document 1). However, the coarse particles present with a small percentage in the particulate formulation due to so wideness of the particle diameter distribution causes a problem of instability of a suspension thereof, i.e., a problem of low dispersivity of the particulate formulation.
For example, as one of methods for finely-milling the organic compound to the level of nano-powder with a narrow particle diameter distribution, a method for milling the organic compound by a bead mill using beads made of ceramic, glass, or the like is well known (for example, see Patent Document 2). Nano-powder with a narrow particle diameter distribution can be obtained by applying such a mechanical impact or a grinding force to the particles of the organic compound. In addition, a wet milling method for milling the organic compound in organic liquid using salt particles as a milling medium is also known (for example, see Patent Documents 3 and 4). The method using salt particles is more advantageous than the method using the beads in view of less contamination with impurities coming from a milling medium. While the impurities coming from the beads are difficult to remove, the impurities coming from the salt particles are easy to remove by a water-washing process (also called salt-removing process) due to high water solubility of salt.